This application claims the benefit of U.S. Provisional Application No. 60/019,977 filed Jun. 17, 1996.
The present invention relates to novel heterocyclylmethyl amino derivatives of cyclobutene 3-4-diones having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of disorders associated with smooth muscle contraction via potassium channel modulation. Such disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, cerebral vascular disease and hypertension.
Stemp et al. (EP-426379) disclose a class of amino substituted cyclobutenedione derivatives of chromans described as having blood pressure lowering activity and bronchodilatory activity. Takeno et al. report a series of diaminocyclobuten-3,4-diones in Public Patent Disclosure Bulletin No. 6-92915. Our own efforts in this area have been disclosed in the following U.S. Pat. Nos. 5,464,867; 5,466,712; 5,403,853; 5,403,854; 5,397,790 and 5,401,753. Several series of 1-amino-2-phenylalkylamino-cyclobutene-3,4-diones are reported as H-2 receptor antagonists by Algieri et al. in U.S. Pat. No. 4,390,701. Several related 1-amino-2-phenoxyalkylamino derivatives are disclosed by Nohara et al. in U.S. Pat. No. 4,673,747. Additionally, several related 1-amino-2-pyridyloxyalkylamino derivatives are disclosed by Nohara et al. in EP-177016. The compounds of Nohara et al. are reported as H-2 receptor antagonists.
A 4-pyridinylmethylamino derivative of cyclobutendione was disclosed by Chandrakumar et al. in U.S. Pat. No. 5,354,746 to possess analgesic activity. The compounds of the Chandrakumar series require the presence of a tricyclic dibenzoxazepine moiety. A 3-pyridinylmethylamino derivative of cyclobutendione was disclosed by Ife in EP-112704 and was reported to be an H-2 antagonist. The compounds of the Ife series require the presence of an N'-pyridyl-diamino moiety.
The syntheses of variously substituted 1,2-diamino-cyclobutene-3,4-diones are described in the following publications: Tietze et al., Chem Ber. 1991, 124, 1215; Tietze et al., Bioconjugate Chem. 1991, 2, 148; Ehrhardt et al., Chem. Ber. 1977, 110, 2506, and Neuse et al., Liebigs Ann. Chem. 1973, 619.